bims-resufa 2020-06-14 papers

Issue of 2020–06–14
two papers selected by
Vera Strogolova, Marquette University

EMBO J. 2020 Jun 08. e103912

Multiple pathways coordinate assembly of human mitochondrial complex IV and stabilization of respiratory supercomplexes.

Teresa Lobo-Jarne, Rafael Pérez-Pérez, Flavia Fontanesi, Alba Timón-Gómez, Ilka Wittig, Ana Peñas, Pablo Serrano-Lorenzo, Inés García-Consuegra, Joaquín Arenas, Miguel A Martín, Antoni Barrientos, Cristina Ugalde.

Mitochondrial respiratory chain complexes I, III, and IV can associate into larger structures termed supercomplexes or respirasomes, thereby generating structural interdependences among the individual complexes yet to be understood. In patients, nonsense mutations in complex IV subunit genes cause severe encephalomyopathies randomly associated with pleiotropic complex I defects. Using complexome profiling and biochemical analyses, we have explored the structural rearrangements of the respiratory chain in human cell lines depleted of the catalytic complex IV subunit COX1 or COX2. In the absence of a functional complex IV holoenzyme, several supercomplex I+III2 species coexist, which differ in their content of COX subunits and COX7A2L/HIGD2A assembly factors. The incorporation of an atypical COX1-HIGD2A submodule attenuates supercomplex I+III2 turnover rate, indicating an unexpected molecular adaptation for supercomplexes stabilization that relies on the presence of COX1 independently of holo-complex IV formation. Our data set the basis for complex I structural dependence on complex IV, revealing the co-existence of alternative pathways for the biogenesis of "supercomplex-associated" versus individual complex IV, which could determine physiological adaptations under different stress and disease scenarios.

Keywords: mitochondrial biogenesis; mitochondrial complex IV assembly; mitochondrial respiratory chain; respirasomes; respiratory supercomplex stabilization

DOI: https://doi.org/10.15252/embj.2019103912

Biochim Biophys Acta Bioenerg. 2020 Jun 09. pii: S0005-2728(20)30089-X. [Epub ahead of print] 148239

Identifying the proton loading site cluster in the Ba3 cytochrome c oxidase that loads and traps protons.

Xiuhong Cai, Chang Yun Son, Junjun Mao, Divya Kaur, Yingying Zhang, Umesh Khaniya, Qiang Cui, M R Gunner.

Cytochrome c Oxidase (CcO) is the terminal electron acceptor in aerobic respiratory chain, reducing O2 to water. The released free energy is stored by pumping protons through the protein, maintaining the transmembrane electrochemical gradient. Protons are held transiently in a proton loading site (PLS) that binds and releases protons driven by the electron transfer reaction cycle. Multi-Conformation Continuum Electrostatics (MCCE) was applied to crystal structures and Molecular Dynamics snapshots of the B-type Thermus Thermophilus CcO. Six residues are identified as the PLS, binding and releasing protons as the charges on heme b and the binuclear center are changed: the heme a3 propionic acids, Asp287, Asp372, His376 and Glu126B. The unloaded state has one proton and the loaded state two protons on these six residues. Different input structures, modifying the PLS conformation, show different proton distributions and result in different proton pumping behaviors. One loaded and one unloaded protonation states have the loaded/unloaded states close in energy so the PLS binds and releases a proton through the reaction cycle. The alternative proton distributions have state energies too far apart to be shifted by the electron transfers so are locked in loaded or unloaded states. Here the protein can use active states to load and unload protons, but has nearby trapped states, which stabilize PLS protonation state, providing new ideas about the CcO proton pumping mechanism. The distance between the PLS residues Asp287 and His376 correlates with the energy difference between loaded and unloaded states.

Keywords: Cytochrome c oxidase; MCCE; Monte Carlo sampling; Proton affinity

DOI: https://doi.org/10.1016/j.bbabio.2020.148239